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The Journal of Neuroscience, July 22, 2009, 29(29):9244-9254; doi:10.1523/JNEUROSCI.1532-09.2009

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Neurobiology of Disease
Haploinsufficiency of AFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration

Francesca Maltecca,^1,3 * Raffaella Magnoni,^1,3 * Federica Cerri,² Gregory A. Cox,⁴ Angelo Quattrini,² and Giorgio Casari^1,3

¹Human Molecular Genetics Unit, Center for Genomics, Bioinformatics, and Biostatistics, ²Unit of Neuropathology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, and ³San Raffaele University, 20132 Milan, Italy, and ⁴The Jackson Laboratory, Bar Harbor, Maine 04609

Correspondence should be addressed to Prof. Giorgio Casari, San Raffaele University and San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. Email: casari.giorgio{at}hsr.it

Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, named m-AAA proteases. These complexes ensure protein quality control in the inner membrane, jointly with a chaperone-like activity on the respiratory chain complexes. Despite coassembling in the same complex, mutations of either paraplegin or AFG3L2 cause two different neurodegenerative disorders. Indeed, mutations of paraplegin are responsible for a recessive form of hereditary spastic paraplegia, whereas mutations of AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28). In this work, we report that the mouse model haploinsufficient for Afg3l2 recapitulates important pathophysiological features of the human disease, thus representing the first SCA28 model. Furthermore, we propose a pathogenetic mechanism in which respiratory chain dysfunction and increased reactive oxygen species production caused by Afg3l2 haploinsufficiency lead to dark degeneration of Purkinje cells and cerebellar dysfunction.

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Received March 24, 2009; revised June 10, 2009; accepted June 13, 2009.

Correspondence should be addressed to Prof. Giorgio Casari, San Raffaele University and San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. Email: casari.giorgio{at}hsr.it

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